WO1994016691A1 - Nitroglycerine-containing plaster, process for producing the same and its use - Google Patents

Nitroglycerine-containing plaster, process for producing the same and its use Download PDF

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Publication number
WO1994016691A1
WO1994016691A1 PCT/EP1994/000053 EP9400053W WO9416691A1 WO 1994016691 A1 WO1994016691 A1 WO 1994016691A1 EP 9400053 W EP9400053 W EP 9400053W WO 9416691 A1 WO9416691 A1 WO 9416691A1
Authority
WO
WIPO (PCT)
Prior art keywords
reservoir
nitroglycerin
active substance
resins
plaster according
Prior art date
Application number
PCT/EP1994/000053
Other languages
German (de)
French (fr)
Inventor
Reinhold Meconi
Tina Rademacher
Original Assignee
Lts Lohmann Therapie-Systeme Gmbh & Co. Kg
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US08/492,004 priority Critical patent/US5670164A/en
Application filed by Lts Lohmann Therapie-Systeme Gmbh & Co. Kg filed Critical Lts Lohmann Therapie-Systeme Gmbh & Co. Kg
Priority to EP94904650A priority patent/EP0680319B1/en
Priority to JP6516613A priority patent/JPH08505631A/en
Priority to AU58606/94A priority patent/AU687775B2/en
Priority to HU9501966A priority patent/HU220768B1/en
Priority to PL94309602A priority patent/PL174806B1/en
Priority to DE59402070T priority patent/DE59402070D1/en
Priority to KR1019950703007A priority patent/KR960700049A/en
Priority to SK891-95A priority patent/SK279839B6/en
Publication of WO1994016691A1 publication Critical patent/WO1994016691A1/en
Priority to NO952908A priority patent/NO952908L/en
Priority to FI953532A priority patent/FI953532A0/en
Priority to GR970401155T priority patent/GR3023505T3/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7076—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising ingredients of undetermined constitution or reaction products thereof, e.g. rosin or other plant resins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug

Definitions

  • the invention relates to an active substance-containing plaster for the controlled release of nitroglycerin to human or animal skin with a backing layer which is impermeable to the nitroglycerin and a pressure-sensitive adhesive nitroglycerin in a uniform or uniform distribution containing a single or multi-layer reservoir, and the use thereof.
  • Nitroglycerin patches are already known. The production of nitroglycerin patches is problematic in that nitroglycerin is explosive and, as a result, its evaporation and thermal and mechanical loads must be avoided as far as possible.
  • nitroglycerin-containing pressure-sensitive adhesive layer often being produced from a solution.
  • the known plaster-like transdermal therapeutic systems for delivering nitroglycerin produced in this way certainly fulfilled the therapeutic tasks, but are too expensive to manufacture.
  • DE-OS 3222800 (ALZA) describes a nitroglycerin patch, the non-adhesive viscous mass obtainable at room temperature by thickening a nitroglycerin solution with a rheological agent being used as the nitroglycerin-containing matrix.
  • US Pat. No. 3,742,951 (CIBA-GE GY), DP-PS 3315272 and DE-OS 3315245 (LOHMANN / SCHWARZ) also describe simply constructed nitroglycerin plasters with pressure-sensitive matrix materials prepared from solution at room temperature. It is also already known, for example from DE-OS 3642931 (CIBA-GEIGY), to use multi-part nitroglycerin reservoirs.
  • Pressure-sensitive hot melt adhesives are generally known from EP-A2-175562; However, there is no suggestion as to whether and how these have to be selected for drug reservoirs, in particular those containing nitroglycerin.
  • nitroglycerin plasters are described in EP-A 0204968, where a self-adhesive reservoir made of rubber and tackifying resin with nitroglycerin is used.
  • This pressure-sensitive adhesive reservoir is produced from solution, so that here the problem of suctioning off solvent residues and possibly also the evaporation of nitroglycerin which occurs therewith occurs.
  • the coating is associated with great difficulties because of the high viscosity of the coating composition. Due to the polymeric compounds contained in the nitroglycerin-containing adhesive (e.g. ethylene-vinyl acetate copolymers), the viscosity is so high that the production of the plasters containing nitroglycerin encounters extremely great problems.
  • the polymeric compounds contained in the nitroglycerin-containing adhesive e.g. ethylene-vinyl acetate copolymers
  • the solution to the problem is to obtain processable melts by using only resins, without using polymeric compounds.
  • soft resins are tackifying resins which are semi-solid or liquid at room temperature or melt up to about 60 ° C. These include, for example, methyl esters of resin acids, methyl esters of hydrogenated resin acids, triethylene glycol esters of hydrogenated resin acids, hydroabietyl alcohol, phthalic acid esters of hydroabiety alcohol, aromatic hydrocarbon resins, low molecular weight styrene resins and hydrogenated hydrocarbon resins.
  • Hard resins in the sense of the invention are tackifying resins which are solid at room temperature and soften from approx. 60 ° C.
  • modified resin acids include modified resin acids, hydrogenated and non-hydrogenated resin esters, polymerized resin esters, acid-modified resin esters, aromatic and aliphatic hydrocarbon resins, alpha-methylstyrene resins, alpha-methylstyrene / vinyltoluene copolymer resins and hydrogenated hydrocarbon resins.
  • the proportion of tackifying resins in the nitroglycer-containing adhesive is 10-43% by weight.
  • the nitroglycerin-containing reservoir also contains plasticizers. Suitable plasticizers are known to the person skilled in the art and are described, for example, in DE-3743946.
  • the nitroglycerin-containing reservoir usually contains plasticizers in a proportion of 0.1-5% by weight.
  • Anti-aging agents in a concentration of 0.1 - 2 ⁇ & vr. -% contain. These are known to the person skilled in the art and e.g. described in DE-3743946.
  • the materials for the impermeable backing layer and the removable protective layer are also known to the person skilled in the art (e.g. DE-3843239).
  • a particularly preferred construction of the transdermal nitroglycerin plaster is the matrix system, in which, as is known, the matrix takes over the control for the release of the substance and this obeys the Higuchi Vt law. However, this does not mean that the membrane system is also indicated in special cases.
  • a membrane controlling the release of nitroglycerin is attached between the reservoir and the pressure-sensitive adhesive layer. In the event that the reservoir is not sufficiently sticky to the skin, it can be provided with a layer of pressure-sensitive adhesive. In this way it is ensured that the transdermal patch adheres to the skin over the entire application period.
  • the thickness of the transdermal patch depends on the therapeutic requirements and can be adapted accordingly. It is usually in the range of 0.03-0.4 mm.
  • the production of the transdermal patch is particularly simple.
  • the resins are melted, the remaining reservoir components are added at a temperature of less than 55 ° C. and homogenized by kneading or stirring.
  • the result is reservoir masses with a viscosity of 1320 - 8253 dPa * s.
  • the nitro-glycerol-containing reservoir mass obtained in this way is applied to the removable protective layer and the impermeable backing layer is laminated on.
  • the machine required to manufacture the transdermal patch has only a small footprint and is significantly less expensive than conventional coating systems for processing solvent-based adhesives. It also works at a high speed in the range of approx. 10-50 m per minute. example 1
  • plasticizer medium-chain triglycerides: Miglyol 812 from Dynamit Nobel
  • nitroglycerin-lactose preparation (10% nitroglycerin) are added and homogenized by kneading.
  • the reservoir mass obtained in this way (viscosity: 8253 dPa-s) is coated at 55 ° C. on the removable protective layer (Hostaphan RN 100 coated on one side with silicone (100 ⁇ thick) - from Kalle) in such a way that the reservoir with a basis weight of 175.5 g / m 2 results.
  • the impermeable backing layer (Hostaphan RN 36 (36 ⁇ m thick) - from Kalle) is laminated on top.
  • Example 3 The preparation is carried out as described in Example 1, but according to the preparation formula given in Table 1; Viscosity: 3301 dPas at 55 ° C).
  • Example 3 The preparation is carried out as described in Example 1, but according to the preparation formula given in Table 1; Viscosity: 3301 dPas at 55 ° C).
  • the preparation is carried out as indicated in Example 1, but according to the preparation formula given in Table 1 (viscosity: 1320 dPas at 55 ° C.).
  • the active ingredient release of the 16 cm 2 transdermal patches is determined according to the rotating bottle method described in USP XXII in 0.9% saline solution at 37 ° C. The results are shown in Table 2.

Abstract

A plaster containing an active substance useful to controllably administer nitroglycerine to the skin consists of an impervious backing layer, a reservoir bonded thereto and containing the active substance and a hot-melt type adhesive, as well as a detachable protective layer. The reservoir contains a homogeneous mixture of (a) tackyfying soft and/or hard resins, (b) emollients, and (c) a nitroglycerine composition.

Description

Nitroglycerinhaltiges Pflaster, Verfahren zu seiner Herstellung und Verwendung Patch containing nitroglycerin, process for its production and use
B E S C H R E I B U N GDESCRIPTION
Die Erfindung betrifft ein wirkstoffhaltiges Pflaster zur gesteuerten Abgabe von Nitroglycerin an die menschliche oder tierische Haut mit einer für das Nitroglycerin un¬ durchlässigen Rückschicht und einem haftklebenden Nitrogly¬ cerin in ungleichmäßiger oder gleichmäßiger Verteilung ent¬ haltenden ein- oder mehrschichtigen Reservoir, sowie dessen Verwendung.The invention relates to an active substance-containing plaster for the controlled release of nitroglycerin to human or animal skin with a backing layer which is impermeable to the nitroglycerin and a pressure-sensitive adhesive nitroglycerin in a uniform or uniform distribution containing a single or multi-layer reservoir, and the use thereof.
Nitroglycerinpflaster sind bereits bekannt. Die Herstel¬ lung von Nitroglycerinpflästern ist insofern problematisch, als Nitroglycerin explosiv ist und infolgedessen seine Verdampfung sowie thermische und mechanische Belastungen möglichst vermieden werden müssen.Nitroglycerin patches are already known. The production of nitroglycerin patches is problematic in that nitroglycerin is explosive and, as a result, its evaporation and thermal and mechanical loads must be avoided as far as possible.
Es ist bevorzugt, bei möglichst niedrigen Temperaturen, insbesondere bei Raumtemperatur, zu arbeiten, wobei häufig die nitroglycerinhaltige Haftkleberschicht aus einer Lösung hergestellt wird. Die derart hergestellten bekannten pflasterartigen transdermalen therapeutischen Systeme zur Abgabe von Nitroglycerin erfüllten durchaus die therapeuti¬ schen Aufgaben, sind aber in der Herstellung zu aufwendig.It is preferred to work at the lowest possible temperatures, in particular at room temperature, the nitroglycerin-containing pressure-sensitive adhesive layer often being produced from a solution. The known plaster-like transdermal therapeutic systems for delivering nitroglycerin produced in this way certainly fulfilled the therapeutic tasks, but are too expensive to manufacture.
In der DE-OS 3222800 (ALZA) ist ein Nitroglycerinpflaster beschrieben, wobei als nitroglycerinhaltige Matrix eine bei Raumtemperatur durch Andickung einer Nitroglycerinlösung mit einem rheologischen Mittel erhältliche nicht klebende viskose Masse eingesetzt wird. Auch im US-Patent 3742951 (CIBA-GE GY) sowie der DP-PS 3315272 und DE-OS 3315245 (LOHMANN/SCHWARZ) werden einfach aufgebaute Nitroglycerin- pflaster mit bei Raumtemperatur aus Lösung hergestellten haftklebenden Matrixmaterialien beschrieben. Es ist auch bereits bekannt, z.B. aus der DE-OS 3642931 (CIBA-GEIGY) , mehrteilige Nitroglycerinreservoirs einzusetzen.DE-OS 3222800 (ALZA) describes a nitroglycerin patch, the non-adhesive viscous mass obtainable at room temperature by thickening a nitroglycerin solution with a rheological agent being used as the nitroglycerin-containing matrix. US Pat. No. 3,742,951 (CIBA-GE GY), DP-PS 3315272 and DE-OS 3315245 (LOHMANN / SCHWARZ) also describe simply constructed nitroglycerin plasters with pressure-sensitive matrix materials prepared from solution at room temperature. It is also already known, for example from DE-OS 3642931 (CIBA-GEIGY), to use multi-part nitroglycerin reservoirs.
Aus der EP-A2-175562 sind allgemein Haftschmelzkleber bekannt; dort ist aber keine Anregung dahingehend gegeben, ob und wie diese für Wirkstoffreservoirs, insbesondere sol¬ che, die Nitroglycerin enthalten, ausgewählt werden müssen.Pressure-sensitive hot melt adhesives are generally known from EP-A2-175562; However, there is no suggestion as to whether and how these have to be selected for drug reservoirs, in particular those containing nitroglycerin.
Gattungsgemäße Nitroglycerinpflaster sind in der EP-A 0204968 beschrieben, wobei dort ein selbstklebendes Reservoir aus Kautschuk und klebrigmachendem Harz mit Nitroglycerin eingesetzt wird. Dieses haftklebende Reser¬ voir wird aus Lösung hergestellt, so daß hier also das Problem des Absaugens von Lösemittelresten und ggf. auch der damit erfolgenden Abdampfung von Nitroglycerin auf¬ tritt.Generic nitroglycerin plasters are described in EP-A 0204968, where a self-adhesive reservoir made of rubber and tackifying resin with nitroglycerin is used. This pressure-sensitive adhesive reservoir is produced from solution, so that here the problem of suctioning off solvent residues and possibly also the evaporation of nitroglycerin which occurs therewith occurs.
Die Verwendung von Lösemitteln bei der Haftkleberschicht- herstellung ist aus mehreren Gründen nachteilig. Die Herstellung der Lösungen erfordert einen hohen technischen Aufwand, da die Geräte explosionsgeschützt sein müssen. Für medizinische Zwecke müssen hochreine und damit teure Lösemittel für die Auflösung der Kleber bzw. deren Aus- gangsmaterialien eingesetzt werden. Ein weiteres Problem besteht darin, Lösemittelfreiheit im Pflaster zu erreichen, wofür teure Trocknungs- und Absauganlagen erforderlich sind. Zusätzlich treten Kosten durch Wiedergewinnung und Abscheidung der Lösemittel auf, um Umweltbelastung zu vermeiden. Daneben stellt die Brennbarkeit der Lösemittel, insbesondere beim hier vorliegenden explosiven Wirkstoff ein zusätzliches Risiko dar. Die meisten organischen Lösemittel sind ferner schädlich für den menschlichen Organismus, so daß aufwendige Schutzmaßnahmen für die im Betrieb tätigen Personen getroffen werden müssen. Aus der DE-3743946 ist ein Nitroglycerinpflaster bekannt, das durch Beschichten eines nitroglycerinhaltigen Klebers aus der Schmelze bei 40 - 80°C hergestellt wird.The use of solvents in the production of the pressure-sensitive adhesive layer is disadvantageous for several reasons. The manufacture of the solutions requires a high level of technical effort, since the devices must be explosion-proof. For medical purposes, high-purity and therefore expensive solvents must be used to dissolve the adhesive or its starting materials. Another problem is to achieve freedom from solvents in the pavement, which requires expensive drying and suction systems. In addition, there are costs associated with the recovery and separation of the solvents in order to avoid environmental pollution. In addition, the flammability of the solvents, in particular in the case of the explosive active substance present here, represents an additional risk. Most organic solvents are also harmful to the human organism, so that complex protective measures have to be taken for the people working in the company. DE-3743946 discloses a nitroglycerin patch which is produced by coating a nitroglycerin-containing adhesive from the melt at 40-80 ° C.
Die Praxis hat jedoch gezeigt, daß die Beschichtung mit großen Schwierigkeiten verbunden ist wegen der hohen Visko¬ sität der Beschichtungsmasse. Durch die im nitroglycer¬ inhaltigen Kleber enthaltenen polymeren Verbindungen (z.B. Ethylen-Vinylacetat-Copolymere) ist die Viskosität so hoch, daß die Herstellung der nitroglycerin-haltigen Pflaster auf äußerst große Probleme stößt.Practice has shown, however, that the coating is associated with great difficulties because of the high viscosity of the coating composition. Due to the polymeric compounds contained in the nitroglycerin-containing adhesive (e.g. ethylene-vinyl acetate copolymers), the viscosity is so high that the production of the plasters containing nitroglycerin encounters extremely great problems.
Es ist somit Aufgabe der Erfindung, die oben angeführten Nachteile zu vermeiden und einen solchen Haftschmelzkleber zur Verfügung zu stellen, der eine einwandfreie Verarbei¬ tung im technischen Maßstab ermöglicht.It is therefore the object of the invention to avoid the disadvantages mentioned above and to provide such a hot-melt adhesive which enables perfect processing on an industrial scale.
Die Lösung der Aufgabe besteht darin, unter Verzicht auf polymere Verbindungen durch die alleinige Verwendung von Harzen zu verarbeitbaren Schmelzen zu kommen.The solution to the problem is to obtain processable melts by using only resins, without using polymeric compounds.
Hier bietet sich ein großer Spielraum für die Formulierung des Reservoirs auf der Basis von Schmelzhaftklebern. So ist es möglich, die Nitroglycerin-Zubereitung mit verschie¬ denen Weichharzen abzumischen. Darüberhinaus bestehen auch Möglichkeiten, verschiedene Hartharze oder auch die Kom¬ bination aus Hart- und Weichharzen zu verwenden.There is a great deal of scope here for formulating the reservoir on the basis of hotmelt PSAs. It is thus possible to mix the nitroglycerin preparation with various soft resins. In addition, there are also possibilities to use different hard resins or the combination of hard and soft resins.
Im Sinne der Erfindung sind Weichharze klebrigmachende Harze, die bei Raumtemperatur halbfest oder flüssig sind bzw. bis ca. 60°C schmelzen. Dazu zählen z.B. Methylester von Harzsäuren, Methylester von hydrierten Harzsäuren, Triethylenglycolester von hydrierten Harzsäuren, Hydroabie- tylalkohol, Phthalsäureester von Hydroabietylakohol, aroma¬ tische Kohlenwasserstoffharze, niedermolekulare Styrolharze und hydrierte Kohlenwasserstoffharze. Hartharze im Sinne der Erfindung sind klebrigmachende Harze, die bei Raumtemperatur fest sind und ab ca. 60°C erweichen. Dazu zählen modifizierte Harzsäuren, hydrierte und nicht hydrierte Harzester polymerisierte Harzester säuremodifizierte Harzester aromatische und aliphatische Kohlenwasserstoff arze, Alpha-Methylstyrolharze, Alpha- Methylstyrol/Vinyltoluol-Copolymer-Harze und hydrierte Kohlenwasserstoffharze.For the purposes of the invention, soft resins are tackifying resins which are semi-solid or liquid at room temperature or melt up to about 60 ° C. These include, for example, methyl esters of resin acids, methyl esters of hydrogenated resin acids, triethylene glycol esters of hydrogenated resin acids, hydroabietyl alcohol, phthalic acid esters of hydroabiety alcohol, aromatic hydrocarbon resins, low molecular weight styrene resins and hydrogenated hydrocarbon resins. Hard resins in the sense of the invention are tackifying resins which are solid at room temperature and soften from approx. 60 ° C. These include modified resin acids, hydrogenated and non-hydrogenated resin esters, polymerized resin esters, acid-modified resin esters, aromatic and aliphatic hydrocarbon resins, alpha-methylstyrene resins, alpha-methylstyrene / vinyltoluene copolymer resins and hydrogenated hydrocarbon resins.
Der Anteil an klebrigmachenden Harzen in der nitroglycer- inhaltigen Klebmasse beträgt 10-43 Gew.-%.The proportion of tackifying resins in the nitroglycer-containing adhesive is 10-43% by weight.
Das nitroglycerin-haltige Reservoir enthält zusätzlich Weichmacher. Geeignete Weichmacher sind dem Fachmann bekannt und beispielsweise in der DE-3743946 beschrieben. Das nitroglycerinhaltige Reservoir enthält üblicherweise Weichmacher in einem Anteil von 0,1-5 Gew.-%.The nitroglycerin-containing reservoir also contains plasticizers. Suitable plasticizers are known to the person skilled in the art and are described, for example, in DE-3743946. The nitroglycerin-containing reservoir usually contains plasticizers in a proportion of 0.1-5% by weight.
Üblicherweise sind im wirkstoffhaltigen Reservoir auch Alterungsschutzschmittel in einer Konzentration von 0,1 - 2 ~&vr . -% enthalten. Diese sind dem Fachmann bekannt und z.B. in der DE-3743946 beschrieben.Anti-aging agents in a concentration of 0.1 - 2 ~ & vr. -% contain. These are known to the person skilled in the art and e.g. described in DE-3743946.
Die Materialien für die undurchlässige Rückschicht und die wiederablösbare Schutzschicht sind dem Fachmann ebenso bekannt (z.B. DE-3843239) .The materials for the impermeable backing layer and the removable protective layer are also known to the person skilled in the art (e.g. DE-3843239).
Ein besonders bevorzugter Aubau des transdermalen Nitrogly¬ cerinpflasters ist das Matrixsystem, bei dem bekanntlich die Matrix die Steuerung für die irkstofffreisetzung übernimmt und diese dem V t-Gesetz nach Higuchi gehorcht. Das bedeutet jedoch nicht, daß in besonderen Fällen auch das Membransystem angezeigt ist. Hierbei ist zwischen Reservoir und Haftkleberschicht eine die Nitroglycerin- Freisetzung steuernde Membran angebracht. Für den Fall, daß das Reservoir keine ausreichende Eigen- klebrigkeit zur Haut aufweist, kann dieses mit einer Haft- kleberschicht versehen werden. Auf diese Weise ist gewähr¬ leistet, daß das transdermale Pflaster über den gesamten ApplikationsZeitraum auf der Haut haftet.A particularly preferred construction of the transdermal nitroglycerin plaster is the matrix system, in which, as is known, the matrix takes over the control for the release of the substance and this obeys the Higuchi Vt law. However, this does not mean that the membrane system is also indicated in special cases. Here, a membrane controlling the release of nitroglycerin is attached between the reservoir and the pressure-sensitive adhesive layer. In the event that the reservoir is not sufficiently sticky to the skin, it can be provided with a layer of pressure-sensitive adhesive. In this way it is ensured that the transdermal patch adheres to the skin over the entire application period.
Die Dicke des transdermalen Pflasters richtet sich nach den therapeutischen Erfordernissen und kann entsprechend ange¬ paßt werden. Sie liegt üblicherweise im Bereich von 0,03- 0,4 mm.The thickness of the transdermal patch depends on the therapeutic requirements and can be adapted accordingly. It is usually in the range of 0.03-0.4 mm.
Im Falle nicht ausreichender Eigenklebrigkeit zur Haut besteht eine weitere Möglichkeit, das Reservoir auf der Haut zu fixieren darin, das Reservoir mit einem haftkleben¬ den Rand zu versehen.In the case of insufficient self-stickiness to the skin, a further possibility of fixing the reservoir on the skin is to provide the reservoir with a pressure-sensitive edge.
Die Herstellung des transdermalen Pflasters stellt sich besonders einfach dar. Die Harze werden aufgeschmolzen, die übrigen Reservoir-Bestandteile bei einer Temperatur von weniger als 55°C zugegeben und durch Kneten oder Rühren homogenisiert. Es resultieren Reservoir-Massen mit einer Viskosität von 1320 - 8253 dPa*s. Die so erhaltene nitro¬ glycerinhaltige Reservoir-Masse wird auf die wiederablös¬ bare Schutzschicht aufgetragen und die undurchlässige Rückschicht zukaschiert.The production of the transdermal patch is particularly simple. The resins are melted, the remaining reservoir components are added at a temperature of less than 55 ° C. and homogenized by kneading or stirring. The result is reservoir masses with a viscosity of 1320 - 8253 dPa * s. The nitro-glycerol-containing reservoir mass obtained in this way is applied to the removable protective layer and the impermeable backing layer is laminated on.
Die zur Herstellung des transdermalen Pflasters erforderli¬ che Maschine hat nur einen geringen Platzbedarf und ist deutlich kostengünstiger als übliche Beschichtungsanlagen zur Verarbeitung von lösemittelhaltigen Klebern. Sie arbeitet darüberhinaus mit einer hohen Geschwindigkeit im Bereich von ca. 10-50 m pro Minute. Beispiel 1The machine required to manufacture the transdermal patch has only a small footprint and is significantly less expensive than conventional coating systems for processing solvent-based adhesives. It also works at a high speed in the range of approx. 10-50 m per minute. example 1
11,05 g Weichharz (Hydroabietylalkohol: Handelsname Abitol der Fa. Hercules),11.05 g of soft resin (hydroabietyl alcohol: trade name Abitol from Hercules),
28,74 g Hartharz (aliphatisches Kohlenwasserstoffharz:28.74 g hard resin (aliphatic hydrocarbon resin:
Hercures C der Fa. Hercules) undHercures C from Hercules) and
2,29 g Weichmacher (mittelkettige Triglyceride: Miglyol 812 der Fa. Dynamit Nobel)2.29 g plasticizer (medium-chain triglycerides: Miglyol 812 from Dynamit Nobel)
werden bei 120°C durch Kneten homogenisiert. Die Schmelze wird auf 55°C abgekühlt und anschließend werden 57,47 g Nitroglycerin-Lactose-Zubereitung (10% Nitroglycerin) zugegeben und durch Kneten homogenisiert.are homogenized at 120 ° C by kneading. The melt is cooled to 55 ° C. and then 57.47 g of nitroglycerin-lactose preparation (10% nitroglycerin) are added and homogenized by kneading.
Die so erhaltene wirkstoffhaltige Reservoir-Masse (Viskosi¬ tät: 8253 dPa-s) wird bei 55°C auf die wiederablösbare Schutzschicht (Hostaphan RN 100 einseitig mit Silikon beschichtet (100 μ dick) - Fa. Kalle) so beschichtet, daß das Reservoir mit einem Flächengewicht von 175,5 g/m2 resultiert. Darauf wird die undurchlässige Rückschicht (Hostaphan RN 36 (36 μm dick) - Fa. Kalle) kaschiert.The reservoir mass obtained in this way (viscosity: 8253 dPa-s) is coated at 55 ° C. on the removable protective layer (Hostaphan RN 100 coated on one side with silicone (100 μ thick) - from Kalle) in such a way that the reservoir with a basis weight of 175.5 g / m 2 results. The impermeable backing layer (Hostaphan RN 36 (36 μm thick) - from Kalle) is laminated on top.
Aus dem so erhaltenen Laminat werden 16 cm2 große Pflaster mit abgerundeten Ecken gestanzt.16 cm 2 plaster with rounded corners are punched out of the laminate thus obtained.
Beispiel 2Example 2
Die Herstellung erfolgt wie in Beispiel 1 beschreiben, jedoch nach der in Tabelle 1 angegebenen Herstellformel; Viskosität: 3301 dPa- s bei 55°C) . Beispiel 3The preparation is carried out as described in Example 1, but according to the preparation formula given in Table 1; Viscosity: 3301 dPas at 55 ° C). Example 3
Die Herstellung erfolgt wie in Beispiel 1 angegeben, jedoch nach der in Tabelle 1 angegebenen Herstellformel (Viskosi¬ tät: 1320 dPa- s bei 55°C) .The preparation is carried out as indicated in Example 1, but according to the preparation formula given in Table 1 (viscosity: 1320 dPas at 55 ° C.).
AnalytikAnalytics
Die Wirkstofffreisetzung der 16 cm2 großen transdermalen Pflaster wird nach der in der USP XXII beschriebenen Rota- ting bottle-Methode in 0,9%iger Kochsalzlösung bei 37°C bestimmt. Die Ergebnisse sind in Tabelle 2 dargestellt. The active ingredient release of the 16 cm 2 transdermal patches is determined according to the rotating bottle method described in USP XXII in 0.9% saline solution at 37 ° C. The results are shown in Table 2.
Tabelle 1: HerstellformelTable 1: Manufacturing formula
Figure imgf000010_0001
Figure imgf000010_0001
Tabelle 2: V/irkstofffreisel:un?Table 2: V / fuel freeze: un?
Figure imgf000010_0002
Figure imgf000010_0002

Claims

Patentanansprüche Claims
1. Wirkstoffhaltiges Pflaster zur kontrollierten Abgabe von Nitroglycerin an die Haut, bestehend aus einer undurch¬ lässigen Rückschicht, einem damit verbundenen, Haftschmelz- kleber und Wirkstoff enthaltenden Reservoir sowie einer wiederablösbaren Schutzschicht, dadurch gekennzeichnet, daß das Reservoir in homogener Mischung enthält:1. Active substance-containing plaster for the controlled release of nitroglycerin to the skin, consisting of an impermeable backing layer, an associated reservoir containing hot-melt adhesive and active substance, and a removable protective layer, characterized in that the reservoir contains in a homogeneous mixture:
a) klebrigmachende Weich- und/oder Hartharze,a) tackifying soft and / or hard resins,
b) Weichmacherb) plasticizers
c) Nitroglycerin-Zubereitung.c) Nitroglycerin preparation.
2. Wirkstoffhaltiges Pflaster nach Anspruch 1, dadurch ge¬ kennzeichnet, daß die klebrigmachenden Harze Weichharze sind.2. Active substance-containing plaster according to claim 1, characterized in that the tackifying resins are soft resins.
3. irkstoffhaltiges Pflaster nach Anspruch 1, dadurch ge¬ kennzeichnet, daß die klebrigmachenden Harze Hartharze sind.3. Irkstoffhaltige plaster according to claim 1, characterized ge indicates that the tackifying resins are hard resins.
4. Wirkstoffhaltiges Pflaster nach Ansprüchen 1 - 3, da¬ durch gekennzeichnet, daß die klebrigmachenden Harze aus einem Gemisch von Weich- und Hartharzen bestehen.4. Active substance-containing plaster according to claims 1-3, characterized in that the tackifying resins consist of a mixture of soft and hard resins.
5. Wirkstoffhaltiges Pflaster nach Ansprüchen 1 - 4, da¬ durch gekennzeichnet, daß der Anteil an klebrigmachen¬ den Harzen zwischen 10 und 43 Gew.-% liegt.5. Active substance-containing plaster according to claims 1-4, characterized in that the proportion of tacky resins is between 10 and 43% by weight.
6. Wirkstoffhaltiges Pflaster nach Ansprüchen 1 - 5, da¬ durch gekennzeichnet, daß das Reservoir 0,3 - 10,0 Gew.-% Nitroglycerin enthält. 6. Active substance-containing plaster according to claims 1-5, characterized in that the reservoir contains 0.3-10.0% by weight of nitroglycerin.
7. irkstoffhaltiges Pflaster nach den Ansprüchen 1 - 6, dadurch gekennzeichnet, daß das Nitroglycerin den vorgemischten Harzen in einer Nitroglycerin-Lactose- Zubereitung hinzugemischt ist.7. plaster of irkstoffhaltiges according to claims 1-6, characterized in that the nitroglycerin is added to the premixed resins in a nitroglycerin-lactose preparation.
8. Wirkstoffhaltiges Pflaster nach Ansprüchen 1 - 7, da¬ durch gekennzeichnet, daß das Reservoir 0, 1 - 5 Gew.-' Weichmacher enthält.8. Active substance-containing plaster according to claims 1-7, characterized in that the reservoir contains 0, 1-5% by weight 'plasticizer.
9. Wirkstoffhaltiges Pflaster nach Ansprüchen 1 - 8, da¬ durch gekennzeichnet, daß das Reservoir 0,1 - 2 Gew.-% Alterungsschutzmittel enthält.9. Active ingredient-containing plaster according to claims 1-8, characterized in that the reservoir contains 0.1-2% by weight of anti-aging agent.
10. Wirkstoffhaltiges Pflaster nach Ansprüchen 1 - 9, da¬ durch gekennzeichnet, daß das Reservoir eine Dicke von 0,03 - 0,4 mm aufweist.10. Active substance-containing plaster according to claims 1-9, characterized in that the reservoir has a thickness of 0.03-0.4 mm.
11. Wirkstoffhaltiges Pflaster nach Ansprüchen 1- 10, da¬ durch gekennzeichnet, daß das Reservoir aus mehreren Schichten besteht.11. Active substance-containing plaster according to claims 1- 10, characterized in that the reservoir consists of several layers.
12. Wirkstoffhaltiges Pflaster nach Ansprüchen 1 - 11, da¬ durch gekennzeichnet, daß das Reservoir im Falle unzu¬ reichender Eigenklebrigkeit zur Haut hin mit einer Haftkleberschicht versehen ist.12. Active ingredient-containing plaster according to claims 1-11, characterized in that the reservoir is provided with a pressure-sensitive adhesive layer in the event of inadequate self-tackiness to the skin.
13. Wirkstoffpflaster nach Ansprüchen 1 - 12, dadurch gekennzeichnet, daß das Reservoir im Falle unzureichen¬ der Eigenklebrigkeit zur Haut mit einem haftklebenden Rand versehen ist.13. Active ingredient plaster according to claims 1-12, characterized in that the reservoir is provided with a pressure-sensitive edge in the event of insufficient self-stickiness to the skin.
14. Verfahren zur Herstellung eines nitroglycennhaltigen Pflasters, dadurch gekennzeichnet, daß das Reservoir aus der Schmelze bei einer Temperatur von weniger als 60°C aufgetragen wird. 14. A method for producing a plaster containing nitroglycene, characterized in that the reservoir is applied from the melt at a temperature of less than 60 ° C.
15. Verwendung des nitroglycerinhaltigen Pflasters nach Ansprüchen 1 - 13 für therapeutische Zwecke in der Human- und Veterinärmedizin. 15. Use of the nitroglycerin-containing patch according to claims 1-13 for therapeutic purposes in human and veterinary medicine.
PCT/EP1994/000053 1993-01-23 1994-01-10 Nitroglycerine-containing plaster, process for producing the same and its use WO1994016691A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
PL94309602A PL174806B1 (en) 1993-01-23 1994-01-10 Nitroglycerin container plaster, method of obtaining same and application thereof
EP94904650A EP0680319B1 (en) 1993-01-23 1994-01-10 Nitroglycerine-containing plaster, process for producing the same and its use
JP6516613A JPH08505631A (en) 1993-01-23 1994-01-10 Method for producing plaster containing nitroglycerin and method of using the same
AU58606/94A AU687775B2 (en) 1993-01-23 1994-01-10 Nitroglycerine-containing plaster, process for producing the same and its uses
HU9501966A HU220768B1 (en) 1993-01-23 1994-01-10 Nitroglycerine-containing plaster and process for producing the same
US08/492,004 US5670164A (en) 1993-01-23 1994-01-10 Nitroglycerin-containing patch, a process for the production and the use thereof
DE59402070T DE59402070D1 (en) 1993-01-23 1994-01-10 PLASTER CONTAINING NITROGLYCER, METHOD FOR THE PRODUCTION AND USE THEREOF
KR1019950703007A KR960700049A (en) 1993-01-23 1994-01-10 NITROGLYCERINE-CONTAINING PLASTER, PROCESS FOR PRODUCING THE SAME AND ITS USE
SK891-95A SK279839B6 (en) 1993-01-23 1994-01-10 Plaster containing an active substance and process for producing the same
NO952908A NO952908L (en) 1993-01-23 1995-07-21 Nitroglycerol-containing resin, method of preparation, and use of the resin
FI953532A FI953532A0 (en) 1993-01-23 1995-07-21 Patches containing nitroglycerol, process for its preparation and its use
GR970401155T GR3023505T3 (en) 1993-01-23 1997-05-21 Nitroglycerine-containing plaster, process for producing the same and its use.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4301781A DE4301781C2 (en) 1993-01-23 1993-01-23 Patch containing nitroglycerin, process for its production and use
DEP4301781.9 1993-01-23

Publications (1)

Publication Number Publication Date
WO1994016691A1 true WO1994016691A1 (en) 1994-08-04

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EP (1) EP0680319B1 (en)
JP (1) JPH08505631A (en)
KR (1) KR960700049A (en)
AT (1) ATE149829T1 (en)
AU (1) AU687775B2 (en)
CA (1) CA2153571A1 (en)
CZ (1) CZ284899B6 (en)
DE (2) DE4301781C2 (en)
DK (1) DK0680319T3 (en)
ES (1) ES2102199T3 (en)
FI (1) FI953532A0 (en)
GR (1) GR3023505T3 (en)
HR (1) HRP940030B1 (en)
HU (1) HU220768B1 (en)
IL (1) IL108233A (en)
MY (1) MY110391A (en)
NO (1) NO952908L (en)
NZ (1) NZ259710A (en)
PH (1) PH31559A (en)
PL (1) PL174806B1 (en)
SI (1) SI9400029A (en)
SK (1) SK279839B6 (en)
WO (1) WO1994016691A1 (en)
YU (1) YU48663B (en)
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DE10234673B4 (en) * 2002-07-30 2007-08-16 Schwarz Pharma Ag Hot-melt TTS for the administration of rotigotine and process for its preparation, and use of rotigotine in the manufacture of a hot-melt TTS
US8246980B2 (en) * 2002-07-30 2012-08-21 Ucb Pharma Gmbh Transdermal delivery system
US8246979B2 (en) 2002-07-30 2012-08-21 Ucb Pharma Gmbh Transdermal delivery system for the administration of rotigotine
US8211462B2 (en) * 2002-07-30 2012-07-03 Ucb Pharma Gmbh Hot-melt TTS for administering rotigotine
DE60204229T2 (en) * 2002-12-02 2006-02-02 Schwarz Pharma Ag Administration of rotigotine for the treatment of Parkinson's disease by iontophoresis
DE10261696A1 (en) 2002-12-30 2004-07-15 Schwarz Pharma Ag Device for the transdermal administration of rotigotine base
EP2921184A1 (en) * 2014-03-19 2015-09-23 LTS LOHMANN Therapie-Systeme AG Finishing plaster having improved tolerability and a long adhesive period and method for producing the same

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HU220768B1 (en) 2002-05-28
AU5860694A (en) 1994-08-15
CZ184195A3 (en) 1996-03-13
SI9400029A (en) 1994-09-30
JPH08505631A (en) 1996-06-18
EP0680319A1 (en) 1995-11-08
CA2153571A1 (en) 1994-08-04
AU687775B2 (en) 1998-03-05
CZ284899B6 (en) 1999-04-14
NO952908D0 (en) 1995-07-21
NZ259710A (en) 1996-06-25
NO952908L (en) 1995-07-21
SK279839B6 (en) 1999-04-13
PH31559A (en) 1998-11-03
ATE149829T1 (en) 1997-03-15
ZA94415B (en) 1994-08-31
GR3023505T3 (en) 1997-08-29
DE4301781A1 (en) 1994-07-28
HRP940030B1 (en) 1999-10-31
PL309602A1 (en) 1995-10-30
SK89195A3 (en) 1996-06-05
FI953532A (en) 1995-07-21
PL174806B1 (en) 1998-09-30
DK0680319T3 (en) 1997-09-01
EP0680319B1 (en) 1997-03-12
IL108233A (en) 1997-08-14
DE59402070D1 (en) 1997-04-17
HUT72983A (en) 1996-06-28
HRP940030A2 (en) 1996-06-30
ES2102199T3 (en) 1997-07-16
FI953532A0 (en) 1995-07-21
YU48663B (en) 1999-06-15
IL108233A0 (en) 1994-04-12
US5670164A (en) 1997-09-23
YU2594A (en) 1996-10-18
MY110391A (en) 1998-04-30
KR960700049A (en) 1996-01-19
DE4301781C2 (en) 1995-07-20
HU9501966D0 (en) 1995-09-28

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